Excerpt

A subset of sensory neurons is characterized by a unique sensitivity to capsaicin, the piquant ingredient in hot chili peppers [1]. The excitation of these nerves by capsaicin (Figure 6.1) is followed by a lasting and fully reversible refractory state, traditionally referred to as desensitization, or, under certain conditions such as neonatal treatment, by gross neurotoxicity [1]. (Parenthetically, carefully executed studies found no morphologic evidence of neurotoxicity by capsaicin at therapeutic doses [2].) Capsaicin evokes these responses by interacting at a specific membrane recognition site, originally termed the vanilloid receptor [1]. The diversity of capsaicin-evoked behavior at the whole animal level has, however, long puzzled scientists. For example, while a clear structure-activity relationship for capsaicin congeners was obtained in the rat eye-wiping assay, it also turned out that pungency was not proportional to the desensitizing effect [3]. Based on these studies, it was postulated that different pharmacophores may be responsible for the excitatory and blocking actions of capsaicinoids [3]. The recognition that resiniferatoxin (RTX; Figure 6.1), a diterpene ester isolated from the latex of the cactuslike plant E. resinifera, functions as an ultrapotent capsaicin analogue with a peculiar spectrum of pharmacological actions has lent further experimental support to this concept [1]. For instance, in the rat RTX can desensitize the pulmonary chemoreflex without any apparent prior excitation, indicating that desensitization may be disconnected from stimulation [4]. This is of great importance, as the initial pain response (excitation) represents the main limitation on the clinical use of vanilloids. In 1990, specific binding of [3H]RTX provided the first direct proof for the existence of a vanilloid receptor [5]. Structure-activity relationships for binding and 45Ca uptake were, however, found to be dissimilar, giving rise to the concept that these responses were mediated by functionally distinct receptors [6]. The molecular cloning of the rat vanilloid receptor, subsequently renamed as the transient receptor potential vanilloid receptor 1 (TRPV1), provided the opportunity to test this hypothesis [7]. It turned out that binding and 45Ca uptake were both mediated by TRPV1 [8]. With this discovery, the research emphasis has shifted to TRPV1 regulation as the mechanism responsible for the reality of the diversity of vanilloid actions. As discussed below, there is now mounting evidence that TRPV1 regulation is amazingly complex and is manifest at many levels, from gene expression through posttranslational modification and formation of receptor homomers to subcellular compartmentalization and association with regulatory proteins. TRPV1 regulation is still only partially understood. Although this regulation has been reviewed exhaustively, the rapid advances in this field necessitate frequent reevaluation of accepted concepts.